US4405782A - Process for the preparation of solutions of 7-aminocephalosporanic acids - Google Patents

Process for the preparation of solutions of 7-aminocephalosporanic acids Download PDF

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Publication number
US4405782A
US4405782A US06/323,403 US32340381A US4405782A US 4405782 A US4405782 A US 4405782A US 32340381 A US32340381 A US 32340381A US 4405782 A US4405782 A US 4405782A
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solution
acid
formula
group
compound
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Alberto Palomo-Coll
Antonio L. Palomo-Coll
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Sandoz Industrial Products SA
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Gema SA
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Priority claimed from ES497076A external-priority patent/ES497076A0/es
Priority claimed from ES504011A external-priority patent/ES8204738A2/es
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Assigned to GEMA, S.A. reassignment GEMA, S.A. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: PALOMO-COLL, ALBERTO, PALOMO-COLL, ANTONIO L.
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Assigned to BIOCHEMIE S.A. reassignment BIOCHEMIE S.A. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: GEMA S.A.
Assigned to BIOCHEMIE, S.A. reassignment BIOCHEMIE, S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: S.A., BIOCHEMIE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids

Definitions

  • the present invention relates to a process for the preparation of solutions of 7-aminocephalosporanic acids, of interest in the manufacture of cephalosporins, antibiotics of use in human and veterinary medicine.
  • the methods known and used in industrial practice for the preparation of solutions of 7-aminocephalosporanic acids consist of reacting one of said acids with a tertiary amine, preferably triethylamine, in an aqueous medium, water-acetone or in methylene chloride.
  • cephalosporins as acids, produce gels on precipitating in an aqueous medium and others are sufficiently soluble in water and require large amounts of organic solvent for their isolation.
  • dichloromethane has become widely used in industry with 7-aminocephalosporanic acid. Nevertheless, with this product at least two equivalents of triethylamine per equivalent of acid are required to obtain solution. The amount of this tertiary amine required is much higher when 1,2-dichloroethane is used.
  • a very peculiar characteristic property of the compounds integrating the group of 7-aminocephalosporanic acids, associated with their purity, is the impossibility of forming solutions with triethylamine in dichloromethane, dimethylformamide, dimethylacetamide and acetonitrile, among other solvents.
  • German Pat. No. 22.63.861 discloses the difficulties of forming triethylamine salts of those acids and their acylation, proposing methanol as appropriate solvent for preparing solutions as triethylamine salts. Although the yields are excellent, the cephalosporin isolation technique is complicated by the need to evaporate the methanol at reduced pressure.
  • German Pat. No. 27.58.000 describe the use of a solution of 7-aminocephalosporanic acid in dichloromethane, in the triethylamine salt form. About three equivalents of triethylamine per equivalent of 7-aminocephalosporanic acid are used in Example 1 (2) and Example 6 is similar for 7-amino-3-(2-amino-1,3,4-thiadiazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid.
  • 3-heterocyclo-2-yl derivatives include the 7-amino-3(1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acids and the derivatives having a 1,3,4-thiazole, 1,3,4-oxadiazole ring in place of the thiadiazole as substituents.
  • No triethylamine solutions were obtained. No solutions were obtained either with compounds having heterocycles condensed to 7-member rings.
  • R 1 may be H or a low molecular weight group such as methoxy or methyl and R 2 a group selected from among hydrogen, methyl, acetoxymethyl, methoxy, chlorine, carbamoyloxymethyl, azido or a thiomethyl, phenylthiomethyl, aliphatic methylthiocarbonyl having from two to four carbon atoms, aromatic methylthiocarbonyl, methylthiocarbonyl heterocyclo derivative having a five or six member ring with at least one atom of oxygen, sulphur or nitrogen, methylthioheterocyclo derivatives of thiazole, thiadiazole, triazole or tetrazole, pyridine, pyrimidine or heterocycles condensed to an aromatic ring, or a thiad
  • the bicyclic amidines of Formula II are known compounds, the properties and use of which in synthesis have been described by Oediger, Moller and Eiter (Synthesis, 591; 1972).
  • 1,5-diazabicyclo (4,3,0) non-5-ene (DBN) and 1,8-diazabicyclo (5,4,0) undec-7-ene (DBU) are commercially obtainable products, particularly DBU which is produced on an industrial scale.
  • C-7 methoxy derivatives of 7-aminocephalosporanic acids of Formula I have been prepared following the process of the Sankyo French patent application No. 75 35-009 with a view to forming the solutions with DBU and DBN; for example 7 beta-amino-7alpha-methoxy-3-(1(1H)tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and 7beta-amino-7alpha-methoxycephalosporanic acid.
  • Other 7-amino-3-heterocyclo-thiomethyl-3-cephem-4-carboxylic acids described by DeMarinis et al. (J. Med. Chem.
  • the corresponding 7-aminocephalosporanic acid of Formula I is suspended in the chosen solvent and, at a temperature of from 5° C. to room temperature there is added gradually the bicyclic amidine of Formula II, with good stirring, until solution is just obtained.
  • the amount of DBN or DBU to be used is determined essentially by the stoichiometry of the reaction, generally at a rate of 1:1 and by the purity of the starting products.
  • the mixed anhydrides of the optically active enamine salts of p-hydroxyphenylglycine and phenylglycine have been effective with pivaloyl chloride and the corresponding chloride of tetrazolylacetic acid.
  • the acids activated with dimethylformiminium chlorosulphite and, in general, the anhydrides and other usual reactants in this art.
  • Solvents appropriate for the purposes of the invention include dichloromethane, 1,2-dichloroethane, dimethylacetamide, acetonitrile, dimethylformamide, and mixtures with methylisobutylketone. Chloroform and nitromethane are also appropriate.
  • An outstanding alternative in the new process consists of preparing the solution of 7-aminocephalosporanic acid of low purity.
  • the impurities are precipitated out as solids or a pasty product by the gradual, controlled addition of methylisobutylketone or 1,2-dimethoxyethane.
  • the clear solution is decanted and the white, high purity 7-aminocephalosporanic acid is precipitated out with acetic acid.
  • the salt may be precipitated out and the impurities remain in the solution; in this case, the salt, preferably the DBU salt, is filtered.
  • An alternative technique to the process of said patent consists of the formation of the solutions at temperatures of -20° to 0° C., by adjusting the amount of bicyclic amidine, DBN and DBU and the like and subsequently adding one equivalent of a triethylamine salt of a weak carboxylic acid such as pivalic acid, 2-ethylhexanoic acid, isononanoic acid and the like.
  • a triethylamine salt of a weak carboxylic acid such as pivalic acid, 2-ethylhexanoic acid, isononanoic acid and the like.
  • the salts of such acids with tertiary bases such as N-methylmorpholine, N-ethylpiperidine, n-tributylamine and the like may be used.
  • the acylation reaction may be conducted within a wide range of temperatures.
  • results 2, 3, 4, 5, 6 and 8 do not occur with the usual methods of using silylating reactants, methanol and isopropanol being excluded in 1 as incompatible solvents, and those of case 1 are conceptually unstable to the humidity when referred to silyl esters.
  • a further important advantage is related to the isolation of the antibiotic.
  • Countless examples describe mixtures of water and miscible organic solvent for preparing triethylamine solutions. The most usual are acetone and tetrahydrofurane. Together with the drawback of a partial hydrolysis of the acylation reactant, the cephalosporins formed are soluble. Therefore a common step to all cases is the distillation of the solvent at reduced pressure and treatments with successive extractions at different pH, representing a complicated technology and losses of yield, all of which is known to the experts in the matter and reflected in the patents.
  • the solutions of bicyclic amidine salts and a 7-aminocephalosporanic acid also reveal the presence of an amino group, at least as active as in the case of the esters and more active than in the N,O-bis-trimethylsilylated compounds in the solvent.
  • the increased activity is determined by the relative acylation capacity and sensitivity to the temperature.
  • the conversion time may be adjusted in each case to obtain the best yields.
  • a comparison of Examples 21 and 23 with 32 show the absence of alteration at very extended and short times.
  • Example 31 proves that the reaction may be effectively performed at moderate temperatures, with better yields than those of Example 17 of German Pat. No. 2263861, where the reaction is held for 1 hour at -35° and 3 hours at -20° C.
  • German Pat. No. 27.58.000 describes the acylation reaction with a solution of 7-aminocephalosporanic acid and triethylamine, Example 6, gives a solution which may not be reproduced with the technically pure product.
  • the following reaction with the 1-(alpha-sin-methoxymino-alpha(2-amino-tiazol-4-yl)acetoxy)-benzotriazole was conducted with low efficiency.
  • better yields than disclosed in those Examples are obtained with the use of the solutions whose preparation is disclosed herein.
  • better results are also obtained with these bicyclic amidine salts than those disclosed in Swiss Pat. No. 535.261 and in those described in the scientific literature (for example, Nannini et al., loc. cit.).
  • active forms include the acid anhydride, the mixed anhydride of weak or strong acids, such as a monoester of carbonic acid, alkyl or arylsulphonic and hindered acids such as trimethylacetic acid, trichloroacetic acid and diphenylacetic acid.
  • an azide of an acid, an active ester or active thioester (example, p-nitrophenol, 2,4-dinitrophenol, thiophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotiazole); the acid itself may be incorporated with the aid of dimethylformiminium chlorosulphite, N,N'-carbonylimidazole or N,N'-carbonylditriazole and carbodiimides (particularly N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or N-cyclohexyl-N'-(2-morpholinethyl)carbodiimide; Sheehan and Hess, J.
  • the active amides such as the azolides or in which the nitrogen atom is a member of a quasiaromatic ring of five members containing at least two atoms of nitrogen, for example, imidazoles, pyrazoles, triazoles, benzimidazoles, benzotriazoles and the substituted derivatives thereof as also condensed heterocycles may be used.
  • Active forms of carboxylic acids also include mixed anhydrides of phosphorous compounds. All of them are widely known and described in the scientific and technical literature.
  • Example 2 To a suspension of 21.42 g of the compound of the title in a mixture of solvents as per Example 2, there was added a sufficient amount, between 100 and 200 ml, of methylisobutylketone, at a temperature of 0°-5° C. to cause the separation of impurities. The liquids were decanted, the pH was adjusted with acetic acid (neutralisation of the DBU) and the white, crystalline 7-ADCA precipitate, after filtration, washing with acetone and drying, was treated as in Example 2.
  • acetic acid neutralisation of the DBU
  • the solution was stirred for 90 minutes at 0°-5° C.
  • the reaction mixture was raised to 15° C. and 325 ml of water were added with a few drops of a sodium dioctylsulphosuccinate solution.
  • the mixture at pH 3.5 (at 20° C.) develops in one minute to pH 3.8 at 20° C., and drops after about 15 minutes to pH 3.63 (22° C.).
  • the slight brown precipitate (0.50 g) was isolated.
  • the water phase was decanted off and decoloured with 2.5 g of active carbon for 15 minutes, the pH being 4.48.
  • the mixture was filtered (a 0.025 g portion of the product was isolated from the carbon with an aqueous triethylamine solution).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
US06/323,403 1980-11-22 1981-11-20 Process for the preparation of solutions of 7-aminocephalosporanic acids Expired - Lifetime US4405782A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ES497076A ES497076A0 (es) 1980-11-22 1980-11-22 Procedimiento para la preparacion de soluciones de acidos 7-aminocefalosporanicos
ES497.076 1980-11-22
ES504011A ES8204738A2 (es) 1981-07-16 1981-07-16 Procedimiento para la preparacion de soluciones de acidos 7-aminocefalosporanicos
ES504.011 1981-07-16

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US4405782A true US4405782A (en) 1983-09-20

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US (1) US4405782A (fr)
EP (1) EP0053077B1 (fr)
CA (1) CA1173824A (fr)
DE (1) DE3174735D1 (fr)
DK (1) DK165118C (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659814A (en) * 1983-05-26 1987-04-21 Gema, S.A. Salts of amino-beta-lactamic acids and process for the preparation thereof
US4716227A (en) * 1984-11-15 1987-12-29 Hoffmann-La Roche Inc. Process for manufacturing cephalosporin esters
US5578721A (en) * 1994-07-11 1996-11-26 Lupin Laboratories Limited Process for preparation of 3-exomethylene cepham sulfoxide esters
US5604222A (en) * 1993-12-27 1997-02-18 Lupin Laboratories, Ltd. Method for the preparation of 2-chloro sulfinyl azetidinones
US20030108499A1 (en) * 2001-07-18 2003-06-12 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Deodorant compositions
CN105541870A (zh) * 2016-02-01 2016-05-04 中山市金城道勃法制药有限公司 一种原研制品质头孢唑啉钠的制备方法及其药物制剂

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT400717B (de) * 1993-07-30 1996-03-25 Biochemie Gmbh Neue guanidin- und amidinsalze von 7-amino-3- hydroxymethyl-3-cephem-4-carbonsäure
AT411996B (de) 2000-09-11 2004-08-26 Sandoz Ag Verfahren zur herstellung von cefuroxim in der form seines n-butylammoniumsalzes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3965098A (en) * 1972-11-29 1976-06-22 American Home Products Corporation Intermediates for preparing cephalosporins and methods of production
US4051131A (en) * 1972-11-29 1977-09-27 American Home Products Corporation (Del.) Intermediates for preparing cephalosporins

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2758000A1 (de) * 1977-12-24 1979-07-05 Hoechst Ag Verfahren zur herstellung von penicillinen und cephalosporinen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3965098A (en) * 1972-11-29 1976-06-22 American Home Products Corporation Intermediates for preparing cephalosporins and methods of production
US4051131A (en) * 1972-11-29 1977-09-27 American Home Products Corporation (Del.) Intermediates for preparing cephalosporins

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659814A (en) * 1983-05-26 1987-04-21 Gema, S.A. Salts of amino-beta-lactamic acids and process for the preparation thereof
US4716227A (en) * 1984-11-15 1987-12-29 Hoffmann-La Roche Inc. Process for manufacturing cephalosporin esters
US5604222A (en) * 1993-12-27 1997-02-18 Lupin Laboratories, Ltd. Method for the preparation of 2-chloro sulfinyl azetidinones
US5578721A (en) * 1994-07-11 1996-11-26 Lupin Laboratories Limited Process for preparation of 3-exomethylene cepham sulfoxide esters
US20030108499A1 (en) * 2001-07-18 2003-06-12 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Deodorant compositions
CN105541870A (zh) * 2016-02-01 2016-05-04 中山市金城道勃法制药有限公司 一种原研制品质头孢唑啉钠的制备方法及其药物制剂

Also Published As

Publication number Publication date
DE3174735D1 (en) 1986-07-03
EP0053077A3 (en) 1983-02-09
DK165118C (da) 1993-03-01
DK508881A (da) 1982-05-23
CA1173824A (fr) 1984-09-04
EP0053077B1 (fr) 1986-05-28
EP0053077A2 (fr) 1982-06-02
DK165118B (da) 1992-10-12

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